The Signal Transduction Program (STRP) has evolved from the antecedent Breast Cancer Research Program (BCRP). This change was accomplished with recognition that signaling molecules are now the leading targets for novel cancer therapies and that these targets transcend boundaries of individual diseases like breast cancer. STRP faculty share an interest in understanding signal transduction processes for the purpose of developing novel cancer therapies. Towards this end, the STRP capitalizes on the quality of fundamental signal transduction research at Yale, and the growing translational importance of signal transduction molecules as cancer therapeutic targets. During the last project period, several receptor and non-receptor tyrosine kinases emerged as validated targets for FDA-approved drugs. Research by the STRP will identify new therapeutic targets among receptors and the pathways they regulate, and facilitate best use of these drugs through personalized medicine. The overall goal of the STRP is to foster basic research leading to rapid therapeutic development in major areas of Signal Transduction research, 1) Signal Transduction;2) Intracellular Signaling Pathways;3) Cell Polarization and the Cytoskeleton;and 4) Subcellular Protein Trafficking. These goals will be achieved through the monthly STRP meetings;through Pilot/Developmental awards that foster new approaches, hew collaborations, and translational work;through the annual retreat;through integration with the Developmental Therapeutics Program for streamlined translational development;and by cross-fertilization with other Programs of the YCC. The co-Leader, Dr. Joseph Schlessinger, has made unparalleled contributions in elucidation of growth factor receptor signal transduction, and in development of structure-based anti-cancer drugs that inhibit signal transduction molecules. Dr. David F. Stern continues as co-leader from the precursor BCRP from which the STRP developed. Dr. Stern has made important advances in understanding HER2/ErbB2 that have facilitated the rapid development of anti-HER2 drugs, and he has long been interested in rational molecular diagnostics based on principles of signal transduction. The distinguished faculty of this program of 26 members includes two members of both the National Academy of Sciences and the Institute of Medicine, several members of the American Academy of Arts &Sciences and EMBO, NIH MERIT award recipients, and the Assoc. Director for Basic Science of the YCC. Program expertise encompasses fundamental aspects of signal transduction, integrins and cortical cytoskeleton, and protein trafficking and sorting. An important goal will be the generation of novel ideas through increased communication of signal transduction biologists with cell structure/trafficking experts. In the last grant period, members of the BCRP or STRP published 365 cancerrelated papers, of which 4.4% represented intraprogrammatic collaborations, and 20.8% were interprogrammatic. (A number of joint publications are not listed since they predate YCC membership). The STRP presently has twenty-five members from nine departments, with total research funding of $11.3 million direct costs ($16.4 million total), $1.7 million direct costs ($2.8 million total) is NCI-funded and $8.0 million direct costs ($11.8 million total) is other peer-reviewed.